During the development of periodontal disease, the junctional epithelium undergoes an aberrant migration over the tooth surface. In addition, a pocket is formed between the tooth and epithelium which can harbor bacteria. A combination of bacterial infection and inflammation results in epithelial and connective tissue destruction, leading to loosening of a tooth and eventual tooth loss. We propose that the migration of epithelial cells which is part of the pathology of periodontal disease involves modulation in those elements of the cytoskeleton, cell-cell and cell-matrix adhesive machinery which contribute to epithelial tissue homeostasis. To this end, in this application, we intend to study the dynamics and functions of the keratin elements of the cytoskeleton, desmosomal and hemidesmosomal cell junctions and a laminin component of the extracellular matrix. The proposal details a multidisciplinary, interdependent series of studies from four investigators at Northwestern University Medical School. Project 1, "Laminin-5 and hemidesmosomes in oral epithelial cells" will involve identification of the functional domains of laminin-5 and its role in nucleation of assembly of hemidesmosomes which tether oral epithelial cells to the tooth surface and to the gingival connective tissue. In addition, the nature of laminin-5-cell surface interactions will be evaluated. In Project 2, "Effect of laminin-5 processing on oral epithelial cells", normal processing of laminin-5 as well as its degradation via proteinases present in the oral cavity will be studied. Analyses of the function of laminin-5 fragments that result from matrix degradation will be evaluated at the cell biological level. Project 3, "Cytoskeletal-cell surface interactions in oral epithelia cells" will investigate the dynamic aspects of keratin networks in oral epithelial cells and the molecular mechanisms underlying keratin- cell surface associations. In Project 4, "Cell-cell junction structure and dynamics in oral epithelia", molecular genetic approaches will be used to investigate protein-protein interactions in desmosomes which link oral epithelial cells together into sheets. In addition, growth factor and proteinase regulation of junction structure will be studies. These studies are expected to provide new insights into the role of cytoskeletal, junctional and matrix proteins in the maintenance of oral epithelial tissue integrity and their potential contribution to the development of periodontal disease.